IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart

• Published in: The Journal of immunology (1950) 2005-01, Vol.174 (1), p.261-269
• Main Authors: Fairweather, DeLisa, Frisancho-Kiss, Sylvia, Yusung, Susy A, Barrett, Masheka A, Davis, Sarah E, Steele, Ronelle A, Gatewood, Shannon J L, Rose, Noel R
• Format: Article
• Language: English
• Subjects: Animals; Coxsackievirus B3; Coxsackievirus Infections - immunology; DNA-Binding Proteins - deficiency; Enterovirus B, Human - immunology; Flow Cytometry; Interferon-gamma - deficiency; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-12 - deficiency; Interleukin-12 - immunology; Interleukin-12 Subunit p35; Macrophages - immunology; Mice; Myocarditis - immunology; Myocarditis - virology; Neutrophils - immunology; Protein Subunits - deficiency; Protein Subunits - immunology; Receptors, Tumor Necrosis Factor, Type I - deficiency; STAT4 Transcription Factor; Trans-Activators - deficiency; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.1.261

Th1-type immune responses, mediated by IL-12-induced IFN-gamma, are believed to exacerbate certain autoimmune diseases. We recently found that signaling via IL-12Rbeta1 increases coxsackievirus B3 (CVB3)-induced myocarditis. In this study, we examined the role of IL-12 on the development of CVB3-induced myocarditis using mice deficient in IL-12p35 that lack IL-12p70. We found that IL-12 deficiency did not prevent myocarditis, but viral replication was significantly increased. Although there were no changes in the total percentage of inflammatory cells in IL-12-deficient hearts compared with wild-type BALB/c controls by FACS analysis, macrophage and neutrophil populations were decreased. This decrease corresponded to reduced TNF-alpha and IFN-gamma levels in the heart, suggesting that macrophage and/or neutrophil populations may be a primary source of TNF-alpha and IFN-gamma during acute CVB3 myocarditis. Increased viral replication in IL-12-deficient mice was not mediated by reduced TNFRp55 signaling, because viral replication was unaltered in TNFRp55-deficient mice. However, STAT4 or IFN-gamma deficiency resulted in significantly increased viral replication and significantly reduced TNF-alpha and IFN-gamma levels in the heart, similar to IL-12 deficiency, indicating that the IL-12/STAT4 pathway of IFN-gamma production is important in limiting CVB3 replication. Furthermore, STAT4 or IFN-gamma deficiency also increased chronic CVB3 myocarditis, indicating that therapeutic strategies aimed at reducing Th1-mediated autoimmune diseases may exacerbate common viral infections such as CVB3 and increase chronic inflammatory heart disease.